Parkinson's Disease (PD) is very common and is contracted by approximately 15 out of 10,000 people in the Western world. The age of debut is usually between 55 and 60 years. The disease is characterised by rigidity and tremors caused by a massive loss of nigrostratial neurones and subsequently a lack of dopamine [3,4-dihydroxyphenylethyl-amine] (1). The symptoms of Parkinson's Disease appear upon a loss of approximately 80% of dopamine neurones.
Tyrosine hydroxylase is the enzyme which transforms tyrosine into Levodopa [Levodopa=3-(3,4-dihydroxiphenyl)-L-alanine] (2), which then is metabolised into dopamine by dopadecarboxylase (DDC) both in the brain and in the peripheral circulation. Dopamine is metabolised into 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine and Homovanilic acid (HVA) by the two enzymes monoamino oxidase (MAO) and catechol-o-methyltransferase (COMT) (3).
Levodopa is still the most important treatment for Parkinson's disease and intermittent oral Levodopa treatment achieves good relief of the symptoms at early stages of the disease. In spite of the massive loss of neurones there still is an adequate storage capacity, which makes possible an even release of dopamine into the synaptic spatium during interval dosage. Levodopa given orally is, however, metabolised to 90% in the first passage before reaching the brain. Bioavailability can be increased by simultaneous administration of DDC-inhibitors, such as carbidopa [L-2-hydrazino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid] or benserazide [2-amino-3-hydroxy-N′-(2,3,4-trihydroxybenzyl)propionohydrazide], which both compete with Levodopa for the metabolising DDC—and thus allow more of the administered Levodopa to reach the brain before it is metabolised into dopamine.
Levodopa is a neutral amino acid, which must pass the blood-brain barrier before it reaches the central nervous system. This transport is energy consuming. The half-life of Levodopa is short, 30 to 60 minutes. Under the influence of the enzyme dopadecarboxylase (DDC), the greater part of Levodopa is metabolised into dopamine. This enzyme is found in a number of organs but above all in muscles, red blood cells and in the skin where it is an important component in the formation of melanin pigment (5). Upon the intake of Levodopa alone, more than 90% is metabolised before it reaches the brain (6).
In order to increase the bioavailability of Levodopa, and reduce its secondary effects on the system, Levodopa is therefore given in combination with a decarboxylase inhibitor (benserazide or carbidopa) in the same oral dosage form. In both the intestine and the blood-brain barrier Levodopa has to compete for the enzyme transport with other amino acids from, for example, protein-rich meals (7). The absorption of Levodopa takes place primarily in the proximal third part of the small intestine (8). Variations in the emptying of the ventricle can, therefore, result in large variations in the serum concentration in the same patient despite intake of the same amount of Levodopa. The inhibition of dopadecarboxylase does not, however, increase the half-life for Levodopa very greatly, which points to the metabolising of Levodopa being shunted to the smaller COMT pathway. This leads to the formation of the metabolite 3-0-methyldopa (OMD) which because of its long half-life (9) is accumulated in plasma and reaches manifestly higher levels as compared to Levodopa (10). The metabolite OMD is also a neutral amino acid and can therefore compete with Levodopa for the passage over the two barriers.
Pharmacokinetic and pharmacodynamic problems concerning Levodopa treatment arise after approximately five years of treatment in the form of fluctuations—from dyskinesia (involuntary movements) to akinesia (totally inhibited movements). When clinical fluctuations begin a distinct parallel can be seen between the decreasing plasma concentrations and the declining clinical response to the Levodopa dose administered. Yet, at an advanced stage in the disease rapid “on-off” fluctuations can be seen without any visible relation to the plasma concentration of Levodopa. This can be explained by there being a certain delay of about 90 minutes in the concentration levels between plasma and the central nervous system (CNS), where the CNS concentration is directly correlated to clinical status.
After suffering from the disease for 5-10 years, the storage capacity of the patient has, however, decreased somewhat due to the continuous loss of neurones, and “wearing off” problems occur. At this stage the storage capacity for dopamine is not adequate until the next dose is due, and Levodopa must therefore be administered at shorter intervals.
At a later stage of the disease, fluctuations occur too with both dyskinesia and bradykinesia (partially inhibited movements) in spite of increasingly frequent doses of dopamine, and sometimes seemingly with no relation to the intake of medicine. This is assumed to be caused by hypersensitivity of the postsynaptic dopamine receptors, resulting in a narrowing of the therapeutic window. This entails a much smaller difference between effective dose and overdose.
Levodopa belongs to the group of neutral amino acids and is absorbed by oral administration only in the proximal third of the small intestine via competitive active transport. It has been shown that approximately 10% of the total dose enters the blood circulation. By avoiding protein-rich meals during the daytime, and in close proximity to the individual times of dosage, it is possible to facilitate Levodopa absorption from the intestine and to a certain degree relieve clinical fluctuations. There is not always a direct correlation between the serum concentration of Levodopa and clinical fluctuations. This is probably due to the fact that the passage over the blood-brain barrier also takes place through active transport and even there competes with other neutral amino acids. An overview of the analysis methods for Levodopa has been published (11)
Experimentally it has been possible to show in animals that hypersensitivity of the postsynaptic dopamine receptors takes place upon interval stimulation, as well as it being possible to achieve hyposensitivity with continuous stimulation of these receptors with Levodopa. Such treatment of human patients should bring about a widening of the therapeutic window and a decrease in the clinical fluctuations (12), a treatment strategy that has not been possible, due to the insolubility of Levodopa in aqueous solutions at approximately neutral pH.
Oral dosage forms of Levodopa for treatment of Parkinson's disease have been used since the 1960ies and the progress of the disease and the treatment thereof follows the description above. In order to improve the treatment of the patients new treatment approaches have been developed such as dopamine agonists and enzyme inhibitors. However, these have not been able to solve all the problems encountered with the traditional Levodopa treatment.
A new Levodopa formulation comprising carbidopa in the form of a viscous gel, Duodopa®, has recently become available from NeoPharma AB, Uppsala, Sweden, for treatment of Parkinson's disease. This treatment is given directly to the duodenum with a nasoduodenal probe or with a percutaneous probe. With this system a continuous administration of Levodopa is possible but the limitations of the gastric transport barrier remains.
There are at present no commercially available pharmaceutical preparations for intravenous, subcutaneous or intrathekal administration due to the poor solubility of Levodopa at neutral pH. Large quantities of Levodopa-containing liquid would be required to give a therapeutic effect at a near neutral pH, and further, Levodopa auto-oxidises rapidly. However, the Swedish patent 512 655 describes the preparation of a Levodopa infusion solution containing 5 mg/mL Levodopa as the only active ingredient. The Levodopa is dissolved in HCl and diluted with glucose, but at higher concentrations than 5 mg/mL the Levodopa precipitates. For a daily dosage of e.g. 600 mg Levodopa, a patient would need 120 mL of said infusion solution per day. It would be desirable to have an infusion solution or injection solution that is therapeutically effective in lower daily volumes.